CN107011362A - A kind of synthetic method of lavo-ofloxacin isomeric compound - Google Patents
A kind of synthetic method of lavo-ofloxacin isomeric compound Download PDFInfo
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- CN107011362A CN107011362A CN201710378136.XA CN201710378136A CN107011362A CN 107011362 A CN107011362 A CN 107011362A CN 201710378136 A CN201710378136 A CN 201710378136A CN 107011362 A CN107011362 A CN 107011362A
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- ofloxacin
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- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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Abstract
The invention provides a kind of fluorine 2 of 3 methyl of lavo-ofloxacin isomers () (S) 10, the oxygen 7H pyridos [1 of 3 dihydro 9 (piperazinyl of 4 methyl 1) 7,2,3 de] [the synthetic method of the carboxylic acid of 1,4] benzoxazines 6.This method comprises the following steps：A) prepare compound M1：Using left oxygen fluorine cyclized ester as raw material, nitration reaction is carried out under the conditions of the concentrated sulfuric acid, nitric acid or nitrate；B) prepare compound M2：N methyl piperazines are added into compound M1 and carry out the reaction of contracting piperazine；C) prepare compound M3：The nitro in compound M2 is reduced to amino with reducing agent；D) prepare compound M4：Amino in compound M3 is converted into hydrogen atom；E) lavo-ofloxacin isomers is prepared：Compound M4 is subjected to ester hydrolysis under acid or alkalescence condition.The invention provides a kind of new synthetic method of lavo-ofloxacin isomers, a kind of preparation method of reference substance is provided for lavo-ofloxacin quality research, so as to provide important directive significance to the safe medication of lavo-ofloxacin.
Description
Technical field
The present invention relates to medicinal chemistry arts, and in particular to fluoro- 2, the 3- dihydros -9- of one kind (-)-(S) -3- methyl isophthalic acids 0-
(4- methyl isophthalic acids-piperazinyl) -7- oxygen -7H- pyridos [1,2,3-de]-[synthetic method of 1,4] benzoxazine -6- carboxylic acids.
Background technology
FQNS is achieved huge with its wide spectrum, the antibacterial characteristics of efficient, low toxicity in clinical anti-infective therapy
Big success.Wherein using Ofloxacin, lavo-ofloxacin, lavo-ofloxacin hydrochloride as wherein outstanding representative.
The lavo-ofloxacin that pharmaceutical Co. Ltd develops altogether of Japan the one or three is the wider outstanding kind of occupation rate of market, is changed
Scientific name is：The fluoro- 2,3- dihydros -10- of (-)-(S) -3- methyl -9- (4- methyl isophthalic acids-piperazinyl) -7- oxygen -7H- pyridos [1,2,
3-de]-[Isosorbide-5-Nitrae] benzoxazine -6- carboxylic acids), it is semihydrate, structure is as follows：
The synthesis technique of lavo-ofloxacin is very ripe, and report document is a lot, and wherein final step is reacted with contracting piperazine and synthesized
Lavo-ofloxacin, such as patent EP368410, US4777253, WO2006009374, WO2006070275, CN1594320,
WO2006070275 etc., synthetic route is as follows：
Patent CN102775424 points out that the impurity (1) of position isomery may be produced in above-mentioned preparation technology,
Impurity (1) chemical name：(S)-(-) the fluoro- 2,3- dihydros -3- methyl -9- of -10- (4- methyl isophthalic acids-piperazinyl) -7- oxygen
Generation -7H- pyridos [1,2,3-de]-[1,4] benzoxazine -6- carboxylic acids.This is reclaimed from mother liquor the patent provides one kind miscellaneous
The preparation method of matter.But the impurity content of this in mother liquor is less, the impurity can not be met by the use of the method a large amount of as reference substance
The requirement of preparation.The patent is pointed out to prepare that the material is relatively difficult by the method for chemistry simultaneously, and cost is higher.
It is simple the invention provides a kind of technique in order to solve above-mentioned technical bottleneck, the synthesis side that starting material is easy to get
Method, to meet the preparation to the isomers.So far, it there are no the chemical synthesis process of the document report compound.
The content of the invention
It is an object of the invention to provide a kind of method of chemical synthesis prepare isomers (-)-(S) of lavo-ofloxacin-
The fluoro- 2,3- dihydros -9- of 3- methyl isophthalic acids 0- (4- methyl isophthalic acids-piperazinyl) -7- oxygen -7H- pyridos [1,2,3-de]-[1,4] benzo
Oxazine -6- carboxylic acids).The synthetically prepared obtained lavo-ofloxacin isomers of the present invention can grind for the quality analysis of lavo-ofloxacin
Offer reference substance is studied carefully, so as to lift the quality standard of lavo-ofloxacin.
Lavo-ofloxacin isomers abbreviation 9- piperazine lavo-ofloxacins described in the present invention, shown in structure such as following formula (I)：
(I) that the salt of the isomers of lavo-ofloxacin described in the present invention refers to and the formed salt of acid.
Technical scheme is as follows：
A kind of synthetic method of lavo-ofloxacin isomers, described synthetic method comprises the following steps：
A) prepare compound M1：Using left oxygen fluorine cyclized ester as raw material, carried out under the conditions of the concentrated sulfuric acid, nitric acid or nitrate
Nitration reaction；
B) prepare compound M2：N methyl piperazine is added into compound M1 and carries out the reaction of contracting piperazine；
C) prepare compound M3：The nitro in compound M2 is reduced to amino with reducing agent；
D) prepare compound M4：Amino in compound M3 is converted into hydrogen atom；
E) lavo-ofloxacin isomers is prepared：Compound M4 is subjected to ester hydrolysis under acid or alkalescence condition；
Reaction scheme is as follows：
Wherein, R1 is Me or Et.
In described step a), nitrate is potassium nitrate or sodium nitrate.
In described step b), also added with solvent, described solvent be selected from DMF, dimethyl sulfoxide (DMSO),
1-METHYLPYRROLIDONE, water, ethanol or acetonitrile.Preferred solvent is selected from DMF, 1-METHYLPYRROLIDONE or water.
In described step c), reducing agent is Fe/NH4Cl、Zn/NH4Cl, Fe/ acetic acid, Zn/ acetic acid or sodium hydrosulfite.It is preferred that
Reducing agent is Zn/ acetic acid.
In described step d), amino is converted into hydrogen atom using nitrite, sulfuric acid and reducing agent；Nitrite is
Potassium nitrite or natrium nitrosum；Reducing agent is ethanol or phosphorous acid, and preferably reducing agent is ethanol.
In described step e), acid is sulfuric acid or hydrochloric acid；Alkali is sodium hydroxide, potassium hydroxide, sodium methoxide or caustic alcohol.
Described step e) the lavo-ofloxacin isomers prepared can continue to be prepared into salt, described salt is acetate,
Hydrochloride or trifluoroacetate.
In described step a), the mol ratio of left oxygen fluorine cyclized ester and nitrate is 1:1.5；
In described step b), the mol ratio of M1 and N methyl piperazine is 1:3.
Wherein, the chemical name of each compound of participation reaction is：
Left oxygen fluorine cyclization fat：The fluoro- 2,3- dihydros -8- nitros -7- oxygen -7H- pyridos of (-)-(S) -3- methyl -9,10- two
[1,2,3-de] -1,4- benzoxazines -6- carboxylic acids second (first) ester
Compound M1：The fluoro- 2,3- dihydros -9- of (-)-(S) -3- methyl isophthalic acids 0- (4- methyl isophthalic acids-piperazinyl) -8- nitros -7-
Oxygen -7H- pyridos [1,2,3-de] -1,4- benzoxazine -6- carboxylic acids second (first) ester
Compound M2：The fluoro- 2,3- dihydros -9- of (-)-(S) -3- methyl isophthalic acids 0- (4- methyl isophthalic acids-piperazinyl) -8- nitros -7-
Oxygen -7H- pyridos [1,2,3-de] -1,4- benzoxazine -6- carboxylic acids second (first) ester
Compound M3：The fluoro- 2,3- dihydros -9- of (-)-(S) -3- methyl isophthalic acids 0- (4- methyl isophthalic acids-piperazinyl) -8- amino -7-
Oxygen -7H- pyridos [1,2,3-de] -1,4- benzoxazine -6- carboxylic acids second (first) ester
Compound M4：The fluoro- 2,3- dihydros -9- of (-)-(S) -3- methyl isophthalic acids 0- (4- methyl isophthalic acids-piperazinyl) -7- oxygen -7H- pyrroles
Pyridine simultaneously [1,2,3-de]-[1,4] benzoxazines -6- carboxylic acids second (first) esters.
The present invention has the following technical effect that：Simple, the synthesis side that starting material is easy to get the invention provides a kind of technique
Method, can meet the preparation to the isomers.The synthetically prepared obtained lavo-ofloxacin isomers of the present invention can be left oxygen fluorine
Sha Xing quality analysis research provides reference substance, so as to lift the quality standard of lavo-ofloxacin.
Brief description of the drawings
Fig. 1 is the HPLC figures of lavo-ofloxacin isomers formula (I) compound.
Fig. 2 is lavo-ofloxacin isomers formula (I) compound1HNMR schemes.
Embodiment
The present invention is further elaborated with reference to embodiment, it will be appreciated by those skilled in the art that these embodiments
The present invention is merely to illustrate, but these examples do not constitute any limitation to the present invention.
It is prepared by the compound M1 of embodiment 1
The fluoro- 2,3- dihydros -3- methyl -7- oxygen -7H- pyridos of (-)-(S) -9,10- two are added into 250mL there-necked flasks
[1,2,3-de)-Isosorbide-5-Nitrae-benzoxazine -6- carboxylic acid, ethyl esters 4.5g (14.5mmol), concentrated sulfuric acid 10mL, controlling reaction temperature do not surpass
0 DEG C is crossed, potassium nitrate 2.21g (21.8mmol) is slowly added to.Maintain the temperature at 0~25 DEG C react 2 hours, after completion of the reaction, to
100mL water is added in reaction solution, solid is separated out and filtered, product 4.8g, faint yellow solid, yield 93% are obtained after drying.
The compound M1 of embodiment 2 preparation
The fluoro- 2,3- dihydros -3- methyl -7- oxygen -7H- pyridos of (-)-(S) -9,10- two are added into 250mL there-necked flasks
[1,2,3-de)-Isosorbide-5-Nitrae-benzoxazine -6- carboxylate methyl esters 4.0g (14.5mmol), concentrated sulfuric acid 10mL, controlling reaction temperature do not surpass
Cross at 0 DEG C, be slowly added to sodium nitrate 1.68g (21.8mmol).Maintain the temperature at 0~25 DEG C to react 1 hour, LCMS monitoring reactions
After finishing, 100mL water is added into reaction solution, solid is separated out and filtered, product 4.5g, faint yellow solid, yield are obtained after drying
87%.
The compound M2 of embodiment 3 preparation
3.4g compounds M1 (9.6mmol), DMF 20mL, N methyl piperazine 2.88g are added into 250mL there-necked flasks
(28.80mmol).It is heated to 30 DEG C and is kept for 12 hours at this temperature, reaction completes to pour into water 100mL in backward reaction solution,
Filter and filter cake is washed with water, product 3.6g, faint yellow solid, yield 86%. are obtained after vacuum drying
The compound M3 of embodiment 4 preparation
1.6g compounds M2 (3.68ml), absolute ethyl alcohol 50mL, water 50mL are added into 250mL there-necked flasks.Then add
Iron powder 0.82g (14.73mmol), ammonium chloride 0.78g (14.73mmol) are heated to 85 DEG C and reacted two hours, TLC (dichloros
Methane/methanol=10:1) display reaction is completed, and filtration catalytic agent, filter cake is washed with dichloromethane, is merged filter cake, is concentrated to dryness,
The isolated product of quick preparative liquid chromatography, yellow solid 0.6g, yield 40%.
The compound M3 of embodiment 5 preparation
1.6g compounds M2 (3.68mmol), anhydrous acetic acid 50mL, ethanol 50mL are added into 250mL there-necked flasks.Then
Zinc powder 0.93g (14.73mmol) is added, is heated to 60 DEG C and reacted two hours, TLC (methylene chloride/methanol=10:1) show
Show that reaction is completed, filtration catalytic agent, filter cake is washed with dichloromethane, merge filter cake, be concentrated to dryness, quick preparative liquid chromatography point
From obtaining product, yellow solid 1.3g, yield 86%.
The compound M4 of embodiment 6 preparation
At 0 DEG C, 1.2g compounds M3 (2.96mmol), sulfuric acid 12mL, potassium nitrite are added into 100mL there-necked flasks
0.5g.Keep reacting at 0 DEG C 1 hour, then add ethanol 15.8g (684mmol), be warming up to 70 DEG C of stirring reactions 2 hours, instead
After should finishing, ethanol is removed under reduced pressure, crude product does not purify as yellow oil 2.5g and direct plunges into lower step and use.
The preparation of the lavo-ofloxacin isomers of embodiment 7
2.0g compound M4, sulfuric acid 5mL, water 50mL are added in 100mL there-necked flasks, 80 DEG C is heated to and stirs 12 hours,
After completion of the reaction with 1mol/L sodium hydroxide solution regulation pH to 6.5~7.5, dichloromethane is extracted 3 times, merges organic phase,
Column chromatography (methylene chloride/methanol) obtains product 1.2g, off-white powder, yield 55%.Testing result is as shown in Figure 1, Figure 2.
Fig. 1 is the HPLC figures of lavo-ofloxacin isomers formula (I) compound.
Fig. 2 is lavo-ofloxacin isomers formula (I) compound1HNMR schemes (d6-DMSO, 400MHz).
From Fig. 1, Fig. 2 can be seen that preparation lavo-ofloxacin isomeric compound purity it is higher (>99%), Ke Yiman
Sufficient its is used as the purity requirement that reference substance and its pharmacological toxicology are studied
The preparation of the lavo-ofloxacin isomers acetate of embodiment 8
Lavo-ofloxacin isomers 1.0g, water 10mL are added in 100mL there-necked flasks, acetic acid 1.0g is added, stirring 0.5 is small
When after add ethanol 20ml, filtering, obtain the acetate 0.9g of lavo-ofloxacin isomers.
The preparation of the lavo-ofloxacin isomers hydrochloride of embodiment 9
Lavo-ofloxacin isomers 1.0g, water 10mL are added in 100mL there-necked flasks, hydrochloric acid 3ml is added, stirring 0.5 is small
When after add ethanol 20ml, filtering, obtain the hydrochloride 0.8g of lavo-ofloxacin isomers.
Claims (10)
1. a kind of synthetic method of lavo-ofloxacin isomers, it is characterised in that described synthetic method comprises the following steps：
A) prepare compound M1：Using left oxygen fluorine cyclized ester as raw material, nitrified under the conditions of the concentrated sulfuric acid, nitric acid or nitrate
Reaction；
B) prepare compound M2：N methyl piperazine is added into compound M1 and carries out the reaction of contracting piperazine；
C) prepare compound M3：The nitro in compound M2 is reduced to amino with reducing agent；
D) prepare compound M4：Amino in compound M3 is converted into hydrogen atom；
E) lavo-ofloxacin isomers is prepared：Compound M4 is subjected to ester hydrolysis under acid or alkalescence condition；
Reaction scheme is as follows：
Wherein, R1 is Me or Et.
2. the synthetic method of lavo-ofloxacin isomers according to claim 1, it is characterised in that described step a)
In, nitrate is potassium nitrate or sodium nitrate.
3. the synthetic method of lavo-ofloxacin isomers according to claim 1, it is characterised in that described step b)
In, also added with solvent, described solvent is selected from DMF, dimethyl sulfoxide (DMSO), 1-METHYLPYRROLIDONE, water, second
Alcohol or acetonitrile.
4. the synthetic method of lavo-ofloxacin isomers according to claim 3, it is characterised in that described step b)
In, solvent is selected from DMF, 1-METHYLPYRROLIDONE or water.
5. the synthetic method of lavo-ofloxacin isomers according to claim 1, it is characterised in that described step c)
In, reducing agent is Fe/NH4Cl、Zn/NH4Cl, Fe/ acetic acid, Zn/ acetic acid or sodium hydrosulfite.
6. the synthetic method of lavo-ofloxacin isomers according to claim 5, it is characterised in that described step c)
In, reducing agent is Zn/ acetic acid.
7. the synthetic method of lavo-ofloxacin isomers according to claim 1, it is characterised in that described step d)
In, amino is converted into hydrogen atom using nitrite, sulfuric acid and reducing agent；Nitrite is potassium nitrite or natrium nitrosum；
Reducing agent is ethanol or phosphorous acid.
8. the synthetic method of lavo-ofloxacin isomers according to claim 1, it is characterised in that described step e)
In, acid is sulfuric acid or hydrochloric acid；Alkali is sodium hydroxide, potassium hydroxide, sodium methoxide or caustic alcohol.
9. the synthetic method of lavo-ofloxacin isomers according to claim 1, it is characterised in that by described step e)
The lavo-ofloxacin isomers of preparation continues to be prepared into salt, and described salt is acetate, hydrochloride or trifluoroacetate.
10. the synthetic method of lavo-ofloxacin isomers according to claim 1, it is characterised in that
In described step a), the mol ratio of left oxygen fluorine cyclized ester and nitrate is 1:1.5；
In described step b), the mol ratio of M1 and N methyl piperazine is 1:3.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107586302A (en) * | 2017-11-03 | 2018-01-16 | 梯尔希（南京）药物研发有限公司 | A kind of Ofloxacin impurity D preparation method |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101514208A (en) * | 2008-10-17 | 2009-08-26 | 浙江京新药业股份有限公司 | Green synthesizing process for ofloxacin |
| CN102070650A (en) * | 2011-01-28 | 2011-05-25 | 山东省药品检验所 | Preparation method for levofloxacin-N-oxide |
| CN102775424A (en) * | 2012-07-09 | 2012-11-14 | 浙江司太立制药股份有限公司 | Preparation method for levofloxacin impurity |
| US20160214940A1 (en) * | 2015-01-26 | 2016-07-28 | Vanderbilt University | Negative allosteric modulators of metabotropic glutamate receptor 2 |
-
2017
- 2017-05-24 CN CN201710378136.XA patent/CN107011362B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101514208A (en) * | 2008-10-17 | 2009-08-26 | 浙江京新药业股份有限公司 | Green synthesizing process for ofloxacin |
| CN102070650A (en) * | 2011-01-28 | 2011-05-25 | 山东省药品检验所 | Preparation method for levofloxacin-N-oxide |
| CN102775424A (en) * | 2012-07-09 | 2012-11-14 | 浙江司太立制药股份有限公司 | Preparation method for levofloxacin impurity |
| US20160214940A1 (en) * | 2015-01-26 | 2016-07-28 | Vanderbilt University | Negative allosteric modulators of metabotropic glutamate receptor 2 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107586302A (en) * | 2017-11-03 | 2018-01-16 | 梯尔希（南京）药物研发有限公司 | A kind of Ofloxacin impurity D preparation method |
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